JP4610734B2 - 21-substituted glycosyl steroid compounds - Google Patents

Description

【図面の簡単な説明】
Ｆｉｇ．１は、本発明に係る実施例化合物を示す図である。
Ｆｉｇ．２は、本発明に係る実施例化合物を示す図である。
Ｆｉｇ．３は、本発明に係る実施例化合物を示す図である。
Ｆｉｇ．４は、本発明に係る実施例化合物を示す図である。
Ｆｉｇ．５は、本発明に係る実施例化合物を示す図である。
Ｆｉｇ．６は、本発明に係る実施例化合物を示す図である。
Ｆｉｇ．７は、本発明に係る実施例化合物を示す図である。
Ｆｉｇ．８は、本発明に係る実施例化合物に係る糖供与体を示す図である。
Ｆｉｇ．９は、本発明に係る実施例化合物に係る糖供与体を示す図である。Technical field
The present invention relates to a novel compound in which position 21 of a steroid compound is substituted with an acylated simple sugar.
Background art
The development of a sugar-steroid compound that does not itself have steroid-like activity but is converted to an active form by glycosidase that increases at sites of inflammation such as rheumatism has been published by a research group of Merck [J. Am. Chem. Soc. 1964, 86, 3903-4, FR3627 (1965), GB1015396 (1965)].
However, although the side-effects of steroid compounds are reduced, the sugar-steroid compounds described in the above documents are still insufficient and need to be improved. In fact, the present inventors also synthesized a compound in which a simple sugar was introduced into a steroid and a glycosylsteroid derivative in which the hydroxyl group of the simple sugar was modified with an acetyl group, and studied its pharmacological action. I confirmed that. This is considered to be because, with simple sugars or acetylglycosyl derivatives thereof, aglycone steroids are easily released by glycosidases that are generally ubiquitous in the living body.
In order to improve such a point, the present inventors proposed modifying the hydroxyl group of a simple sugar in a saccharide-steroid compound with a bulky protecting group, and already made an international patent application (International Publication Number: WO95 / 09177). ) According to this invention, the hydroxyl group of a simple sugar in a sugar-steroid compound is, for example, an arylcarbonyl group such as a toluoyl group (ortho, meta or para-methylbenzoyl group) or a benzoyl group, an arylalkyl group such as a benzyl group, or a para -It is modified with a bulky protecting group such as a chlorobenzoyl group. And by doing in this way, the release | extrication of the steroid by glycosidase other than a pathological site | part can be suppressed, and it becomes possible to aim at reduction of a side effect.
Disclosure of the invention
However, from the viewpoint of the development of medicines, it is preferable to further improve by promoting the enhancement of action and reduction of side effects and the separation of action and side effects.
The present invention has been made in view of the above problems, and an object of the present invention is to provide a sugar-steroid compound having a strong anti-inflammatory action and extremely low side effects.
  In the present invention, the hydroxyl group at position 21 of budesonide is modified with a sugar having a protecting group, and the sugar is selected from the group consisting of glucose, galactose, glucuronic acid, mannose, rhamnose and fucose, and the protecting group is toluoyl Group, furoyl group, methylbutyryl group, valeryl group,Tigroyl groupandIsobutyryl groupAn anti-inflammatory agent comprising a budesonide derivative selected from the group consisting of as an active ingredient.
  Specific examples of the anti-inflammatory agent include an anti-inflammatory agent for topical application and an anti-inflammatory agent in the form of a parenteral administration drug, and more specifically, an asthma treatment agent for inhalation administration, and an allergy for nasal administration. Examples include rhinitis therapeutic agents, arthritic therapeutic agents for intraarticular administration or application administration, or anti-inflammatory agents in the form of dermatitis treatment agents for application administration.
  In the examples described later, all of the specific budesonide derivatives that are active ingredients of the anti-inflammatory agent of the present invention exhibit remarkable effects classified into ranks 1 to 4 in Table 4. In addition, the rank 5 and later in Table 4 correspond to comparative examples outside the present invention. The effective amount of the anti-inflammatory agent of the present invention is appropriately determined in consideration of the activity of the compound.
BEST MODE FOR CARRYING OUT THE INVENTION
Any of the pharmaceuticals or anti-inflammatory agents containing the above-mentioned compounds can be used for the outer skin as an ointment, cream, lotion, or tape (external application agent only) alone or in combination. Further, for bronchial asthma and the like, it can be used for intraoral inhalation, and for allergic rhinitis and the like, it can be used for intranasal inhalation.
The compound of the present invention as described above (steroid derivative (glycoside)) not only has a granulomatous growth inhibitory action and a croton oil ear edema inhibitory action, but also body weight, chest weight, spleen weight by drug administration or application. It has little effect on adrenal weight and white blood cell count, and is less toxic and safer than conventional steroids.
The compounds according to the present invention include eczema, dermatitis group (including progressive palmokeratosis, female facial dermatosis, vidar lichen, radioactive dermatitis, sun dermatitis), skin pruritus, prurigo group (renal Measles-like lichen, stromas, fixed urticaria), insect bites, psoriasis, palmoplantar pustulosis, lichen planus, luster lichen, pore erythema, gibberella erythema, erythema ( (Including erythroderma due to malignant lymphoma), chronic discoid lupus erythematosus, drug eruption / addiction eruption, alopecia areata, burns (including scars and keloids), cryosurgery, jurying herpes dermatitis (including pemphigoid) It can be applied to hemorrhoids, tympanoplasty, inner ear fenestration surgery, inner ear radical surgery, colitis and the like.
Here, after protecting the hydroxyl group of the simple sugar or the acylated sugar of the simple sugar with a toluoyl group or an acetyl group, the above compound is halogen-substituted at the anomeric position, molecular sieve, and silver carbonate, It can be obtained by reacting a steroid compound such as budesonide in the presence of a Lewis acid such as silver triflate, silver perchlorate or tin tetrachloride. Deprotection of the above compound can be easily performed by deprotection using MeONa / MeOH, aqueous sodium hydroxide, or the like.
In this case, when a toluoyl group is employed as a protecting group, it is possible not only to prevent the by-production of the orthoester, and not only to obtain the target compound in a good yield but also to the protective body itself obtained thereby. It has the benefit of high safety with few side effects.
Example
<Example 1-1>23R  →1R
Compound23R(100 mg, 0.167 mmol) was dissolved in pyridine (10 mL), acetic anhydride (1 mL) was added with stirring at 0 ° C., and the mixture was stirred at 5 ° C. for 18 hours. Methanol was added to the reaction mixture, and the mixture was stirred for 30 minutes and then dried under reduced pressure. The residue was purified by silica gel column chromatography (60 g, chloroform / methanol, 30: 1)1R(119 mg, 93%) was obtained.
Rf = 0.66 (chloroform: methanol = 20: 1)
¹H-NMR (CDCl₃) Δ (ppm): 6.025 (s, 1H, Bud-4), 5.243 (t, 1H, J = 9.5 Hz, H-3), 5.11 (t, 1H, J = 9. 9 Hz, H-4), 5.022 (dd, 1H, J = 8.1, 9.5 Hz, H-2), 4.856 (d, 1H, J = 8.1 Hz, H-1), 4 .594, 4.544 (2d, 2H, J = 18.7 Hz, 2 × Bud-21), 3.633 (m, 1H, H-5), 2.127, 2.099, 2.047, 2.022 (4s, 12H, 4Ac), 1.469 (s, 3H, Bud-19), 0.919 (t, 3H, J = 7.3 Hz, Bud-25), 0.902 (s, 3H, Bud- 18).
<Example 1-2>23S  →1S
Compound23S(103 mg, 0.174 mmol) was dissolved in pyridine (10 mL), acetic anhydride (1 mL) was added with stirring at 0 ° C., and the mixture was stirred at 5 ° C. for 18 hours. Methanol was added to the reaction mixture, and the mixture was stirred for 30 minutes and then dried under reduced pressure. The residue was purified by silica gel column chromatography (60 g, chloroform / methanol, 30: 1)1S(112 mg, 87%) was obtained.
Rf = 0.75 (chloroform: methanol = 24: 1)
¹H-NMR (CDCl₃) Δ (ppm): 6.018 (s, 1H, Bud-4), 5.245 (t, 1H, J = 9.5 Hz, H-3), 5.105 (t, 1H, J = 9. 5 Hz, H-4), 5.024 (dd, 1H, J = 7.7, 9.5 Hz, H-2), 4.832 (d, 1H, J = 7.7 Hz, H-1), 4 .670, 4.526 (2d, 2H, J = 18.7 Hz, 2 × Bud-21), 4.286 (m, 2H, 2H-6), 3.640 (m, 1H, H-5), 2. 121, 2.104, 2.045, 2.021 (4s, 12H, 4Ac), 1.466 (s, 3H, Bud-19), 0.946 (s, 3H, Bud-18), 0.903 (T, 3H, J = 7.3 Hz, Bud-25).
<Example 2-1>23R  →2R
Compound23R(198 mg, 0.33 mmol) was dissolved in pyridine (10 mL), isobutyryl chloride (320 μL, 3.05 mmol) was added, and the mixture was stirred at room temperature for 18 hours. Methanol was added to the reaction solution, stirred for 30 minutes and then dried under reduced pressure. The residue was purified by silica gel column chromatography (40 g, toluene / ethyl acetate, 2: 1) and then by Sephadex LH-20 (methanol).2R(264 mg, 91%) was obtained.
Rf = 0.46 (toluene: ethyl acetate = 24: 1)
¹H-NMR (CDCl₃) Δ (ppm): 6.025 (s, 1H, Bud-4), 5.308 (t, 1H, J = 9.5 Hz, H-3), 5.158 (t, 1H, J = 9. 9 Hz, H-4), 5.032 (dd, 1H, J = 7.7, 9.5 Hz, H-2), 4.873 (d, 1H, J = 7.7 Hz, H-1), 3 .594 (m, 1H, H-5), 2.65-2.40 (m, 4H, 4xCH (CH₃)₂), 1.471 (s, 3H, Bud-19), 1.209-1.077 (m, 24H, i-Bu), 0.918 (t, 3H, J = 7.3 Hz, Bud-25) , 0.906 (s, 3H, Bud-18).
FAB⁺  Ms Calcd. C₅₁H₇₆O₁₅(928.4), m / z: 951 (M + Na)⁺.
<Example 2-2>23S  →2S
Compound23S(198 mg, 0.33 mmol) was dissolved in pyridine (10 mL), isobutyryl chloride (320 μL, 3.05 mmol) was added, and the mixture was stirred at room temperature for 18 hours. Methanol was added to the reaction mixture, and the mixture was stirred for 30 minutes and then dried under reduced pressure. The residue was purified by silica gel column chromatography (40 g, toluene / ethyl acetate, 2: 1) and then by Sephadex LH-20 (methanol).2S(249 mg, 85%) was obtained.
Rf = 0.64 (chloroform: methanol = 30: 1)
¹H-NMR (CDCl₃) Δ (ppm): 6.018 (s, 1H, Bud-4), 5.311 (t, 1H, J = 9.5 Hz, H-3), 5.143 (t, 1H, J = 9. 5 Hz, H-4), 5.041 (dd, 1H, J = 8.1, 9.5 Hz, H-2), 4.870 (d, 1H, J = 8.1 Hz, H-1), 4 .659, 4.522 (2d, 2H, J = 18.7 Hz, 2 × Bud-21), 3.614 (m, 1H, H-5), 2.65-2.40 (m, 4H, 4 × CH (CH₃)₂), 1.469 (s, 3H, Bud-19), 1.200-0.947 (m, 24H, i-Bu), 0.947 (s, 3H, Bud-18), 0.896 ( t, 3H, J = 7.3 Hz, Bud-25).
FAB⁺  Ms Calcd. C₅₁H₇₆O₁₅(928.4), m / z: 951 (M + Na)⁺.
<Example 3-1>23S  →3S
Compound23S(70 mg, 0.12 mmol) was dissolved in pyridine (5 mL), (S) -2-methylbutyric anhydride (0.14 μL, 0.71 mmol) was added, and the mixture was stirred at room temperature for 1 day. Next, dimethylaminopyridine and anhydrous (S) -2-methylbutyric acid (0.14 μL, 0.7 mmol) were added, and the mixture was stirred at room temperature for 1 day. The temperature was raised to 45 ° C., and the mixture was further stirred for 1 day. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel columnography (toluene: ethyl acetate = 5: 1),3S(71 mg, 65%) was obtained.
Rf = 0.50 (toluene: ethyl acetate = 3: 1)
¹H-NMR (CDCl₃) Δ (ppm): 6.282 (dd, 1H, J = 1.8, 10.3 Hz, Bud-2), 6.020 (s, 1H, Bud-4), 5.330 (t, 1H, J = 9.5 Hz H-3), 5.051 (dd, 1H, J = 8.1, 9.5 Hz, H-2), 4.925 (d, 1H, J = 8.1 Hz, H-1) ), 4.663 (d, 1H, J = 18.7 Hz, Bud-21), 4.520 (d, 1H, J = 18.7 Hz, Bud-21 ′) 4.419 (dd, 1H, J = 3.3, 12.1 Hz, H-6), 4.164 (dd, 1H, J = 3.3, 12.1 Hz, H-6 ′) 3.617 (m, 1H, H-5), 1 .471 (s, 3H, Bud-19).
FAB⁺  Ms Calcd. C₅₁H₇₆O₁₅(928.4), m / z: (M + Na)⁺  951.
<Example 3-2>23R  →3R
Compound 23R (200 mg, 0.34 mmol) was dissolved in pyridine (7 mL), anhydrous (S) -2-methylbutyric acid (0.4 μL, 2.02 mmol) was added, and the mixture was stirred at room temperature for 1 day. Next, dimethylaminopyridine and anhydrous (S) -2-methylbutyric acid (0.4 μL, 2.02 mmol) were added, and the mixture was stirred at room temperature for 1 day. The temperature was raised to 45 ° C., and the mixture was further stirred for 1 day. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel columnography (toluene: ethyl acetate = 5: 1),3R(290 mg, 93%) was obtained.
Rf = 0.52 (toluene: ethyl acetate = 3: 1)
¹H-NMR (CDCl₃) Δ (ppm): 6.291 (dd, 1H, J = 1.8, 9.9 Hz, Bud-2), 6.028 (s, 1H, Bud-4), 5.327 (t, 1H, J = 9.5 Hz, H-3), 5.181 (t, 1H, J = 9.5 Hz, H-4), 5.045 (dd, 1H, J = 7.7, 9.5 Hz, H- 2), 4.911 (d, 1H, J = 8.1 Hz, H-1), 4.895 (d, 1H, J = 5.1 Hz, Bud-22), 4.111 (dd, 1H, J = 3.3, 112.1 Hz, H-6), 3.590 (m, 1H, H-5), 1.474 (s, 3H, Bud-19).
FAB⁺  Ms Calcd. C₅₁H₇₆O₁₅(928.4), m / z: (M + Na)⁺  951.
<Example 4-1>23R  →4R
Compound23R(73 mg, 0.12 mmol) was dissolved in pyridine (5 mL), valeryl chloride (73 μL, 0.62 mmol) was added and stirred at room temperature for 1 day, valeryl chloride (110 μL, 0.92 mmol) was added at room temperature. The mixture was further stirred for 2 days. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel columnography (toluene: ethyl acetate = 5: 1)4R(97 mg, 85%) was obtained.
4R: Rf = 0.34 (toluene: ethyl acetate = 5: 1)
¹H-NMR (CDCl₃) Δ (ppm): 6.284 (dd, 1H, J = 1.8, 10.3 Hz, Bud-2), 6.028 (s, 1H, Bud-4), 5.274 (t, 1H, J = 9.5 Hz, H-3), 5.130 (t, 1H, J = 9.5 Hz, H-4), 5.030 (dd, 1H, J = 8.1, 9.5 Hz, H− 2), 4.885 (d, 1H, J = 4.8 Hz, Bud-22), 4.850 (d, 1H, J = 8.1 Hz, H-1), 4.385 (dd, 1H, J = 3.3, 12.5 Hz, H-6), 4.198 (dd, 1H, J = 3.3, 12.1 Hz, H-6 ′), 3.612 (m, 1H, H-5) , 1.474 (s, 3H, Bud-19).
FAB⁺  MS Calcd. C₅₁H₇₆O₁₅(928.4), m / z: (M + Na)⁺  951.
<Example 4-2>23S  →4S
Compound23S(73 mg, 0.12 mmol) was dissolved in pyridine (5 mL), valeryl chloride (70 μL, 0.59 mmol) was added and stirred at room temperature for 1 day, valeryl chloride (105 μL, 0.89 mmol) was added, and further at room temperature. Stir for 2 days. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel columnography (toluene: ethyl acetate = 5: 1),4S(82 mg, 75%) was obtained.
Rf = 0.34 (toluene: ethyl acetate = 5: 1)
¹H-NMR (CDCl₃) Δ (ppm): 6.277 (dd, 1H, J = 1.8, 10.3 Hz, Bud-2), 6.020 (s, 1H, Bud-4), 5.275 (t, 1H, J = 9.5 Hz, H-3), 5.118 (t, 1H, J = 9.5 Hz, H-4), 5.034 (dd, 1H, J = 8.1, 9.5 Hz, H− 2), 4.837 (d, 1H, J = 7.7 Hz, H-1), 4.661 (d, 1H, J = 18.7 Hz, Bud-21), 4.534 (d, 1H, J = 18.7 Hz, Bud-21 ′), 1.471 (s, 3H, Bud-19).
FAB⁺  MS Calcd. C₅₁H₇₆O₁₅(928.4), m / z: (M + Na)⁺  951.
<Example 5-1>23R  →5R
Compound23R(100 mg, 0.17 mmol) dissolved in pyridine (20 mL), tiglic anhydride (2.6 mL, 2.68 mmol) prepared from tiglic acid and N, N′-dicyclohexylcarbodiimide and a catalytic amount of 4-dimethylaminopyridine And stirred at 60 ° C. for 18 hours. Methanol was added to the reaction solution, stirred for 30 minutes and then dried under reduced pressure. The residue was purified by silica gel column chromatography (130 g, toluene / ethyl acetate, 3: 1) and then by Sephadex LH-20 (methanol).5R(153 mg, 98%) was obtained.
Rf = 0.51 (toluene: ethyl acetate = 2: 1)
¹H-NMR (CDCl₃) Δ (ppm): 6.850 (m, 4H, 4X = CH-CH₃), 6.026 (s, 1H, Bud-4), 5.438 (t, 1H, J = 9.9 Hz, H-3), 5.282 (t, 1H, J = 9.9 Hz, H−) 4), 5.155 (dd, 1H, J = 8.1, 9.9 Hz, H-2), 4.967 (d, 1H, J = 8.1 Hz, H-1), 3.920 (m) , 1H, H-5), 1.90-1.65 (m, 24H, 8X CH₃), 1.480 (s, 3H, Bud-19), 0.930 (s, 3H, Bud-18), 0.911 (t, 3H, J = 7.3 Hz, Bud-25).
FAB⁺  MS Calcd. C₅₁H₇₆O₁₅(920.4), m / z: 943 (M + Na)⁺.
<Example 5-2>23S  →5S
Compound23S(100 mg, 0.17 mmol) dissolved in pyridine (20 mL), tiglic anhydride (2.6 mL, 2.68 mmol) prepared from tiglic acid and N, N′-dicyclohexylcarbodiimide and a catalytic amount of 4-dimethylaminopyridine And stirred at 60 ° C. for 18 hours. Methanol was added to the reaction solution, stirred for 30 minutes and then dried under reduced pressure. The residue was purified by silica gel column chromatography (130 g, toluene / ethyl acetate, 3: 1) and then by Sephadex LH-20 (methanol).5S(154 mg, 99%) was obtained.
Rf = 0.33 (toluene: ethyl acetate = 4: 1)
¹H-NMR (CDCl₃) Δ (ppm): 6.800 (m, 4H, 4X = CH-CH₃), 6.020 (s, 1H, Bud-4), 5.442 (t, 1H, J = 9.5 Hz, H-3), 5.263 (t, 1H, J = 9.9 Hz, H−) 4), 4.941 (d, 1H, J = 8.1 Hz, H-1), 1.90-1.65 (m, 24H, 8X CH₃), 1.481 (s, 3H, Bud-19), 0.968 (s, 3H, Bud-18), 0.893 (t, 3H, J = 7.3 Hz, Bud-25).
FAB⁺  MS Calcd. C₅₁H₇₆O₁₅(920.4), m / z: 943 (M + Na)⁺.
<Example 6-1>23R  →6R
Compound23R(53 mg, 89 μmol) was dissolved in pyridine (20 mL), cyclohexanecarbonyl chloride (131 mg, 0.84 mmol) and a catalytic amount of 4-dimethylaminopyridine were added, and the mixture was stirred at room temperature for 18 hours. Methanol was added to the reaction solution, stirred for 30 minutes and then dried under reduced pressure. The residue was purified by silica gel column chromatography (65 g, toluene / ethyl acetate, 4: 1) and then Sephadex LH-20 (methanol) to give a compound.6R(72 mg, 78%) was obtained.
Rf = 0.52 (toluene: ethyl acetate = 4: 1)
¹H-NMR (CDCl₃) Δ (ppm): 6.028 (s, 1H, Bud-4), 5.273 (t, 1H, J = 9.5 Hz, H-3), 5.143 (t, 1H, J = 9. 5 Hz, H-4), 5.015 (dd, 1H, J = 8.1, 9.5 Hz, H-2), 4.881 (d, 1H, J = 8.1 Hz, H-1), 3 .558 (m, 1H, H-5), 1.471 (s, 3H, Bud-19), 0.918 (t, 3H, J = 7.3 Hz, Bud-25), 0.899 (s, 3H, Bud-18).
<Example 6-2>23S  →6S
Compound23S(77 mg, 0.13 mmol) was dissolved in pyridine (20 mL), cyclohexanecarbonyl chloride (262 mg, 1.79 mmol) and a catalytic amount of 4-dimethylaminopyridine were added, and the mixture was stirred at room temperature for 18 hours. Methanol was added to the reaction solution, stirred for 30 minutes and then dried under reduced pressure. The residue was purified by silica gel column chromatography (65 g, toluene / ethyl acetate, 4: 1) and then Sephadex LH-20 (methanol) to give a compound.6S(107 mg, 80%) was obtained.
Rf = 0.62 (chloroform: methanol = 7: 1)
¹H-NMR (CDCl₃) Δ (ppm): 6.026 (s, 1H, Bud-4), 5.278 (t, 1H, J = 9.5 Hz, H-3), 5.129 (t, 1H, J = 9. 9 Hz, H-4), 5.026 (dd, 1H, J = 8.1, 9.5 Hz, H-2), 4.878 (d, 1H, J = 8.1 Hz, H-1), 3 579 (m, 1H, H-5), 1.470 (s, 3H, Bud-19), 0.940 (s, 3H, Bud-18), 0.896 (t, 3H, J = 7. 7 Hz, Bud-25).
<Example 7-1>23R  →7R
Compound23R(100 mg, 0.17 mmol) was dissolved in pyridine (20 mL), nicotinoyl chloride hydrochloride (238 mg, 1.34 mmol) and a catalytic amount of 4-dimethylaminopyridine were added, and the mixture was stirred at room temperature for 18 hours. Methanol was added to the reaction solution, stirred for 30 minutes and then dried under reduced pressure. The residue was purified by silica gel column chromatography (130 g, chloroform / methanol, 12: 1) and then Sephadex LH-20 (methanol)7R(170 mg, 99%) was obtained.
Rf = 0.60 (chloroform: methanol = 7: 1)
¹H-NMR (CDCl₃) Δ (ppm): 9.30-7.20 (m, 16H, Arom.H), 6.325 (s, 1H, Bud-4), 5.971 (t, 1H, J = 9.5 Hz, H-3), 5.613 (t, 1H, J = 9.9 Hz, H-4), 5.578 (dd, 1H, J = 8.1, 9.5 Hz, H-2), 5.240. (D, 1H, J = 8.1 Hz, H-1), 4.222 (m, 1H, H-5), 1.542 (s, 3H, Bud-19), 1.023 (s, 3H, Bud-18), 0.879 (t, 3H, J = 7.3 Hz, Bud-25).
FAB⁺  Ms Calcd. C₅₅H₅₆N₄O₁₅(1012.3), m / z: 1013 (M + H)⁺.
<Example 7-2>23S  →7S
Compound23S(100 mg, 0.17 mmol) was dissolved in pyridine (20 mL), nicotinoyl chloride hydrochloride (238 mg, 1.34 mmol) and a catalytic amount of 4-dimethylaminopyridine were added, and the mixture was stirred at room temperature for 18 hours. Methanol was added to the reaction solution, stirred for 30 minutes and then dried under reduced pressure. The residue was purified by silica gel column chromatography (200 g, chloroform / methanol, 12: 1) and then by Sephadex LH-20 (methanol).7S(174 mg, 96%) was obtained.
Rf = 0.60 (chloroform: methanol = 7: 1)
¹H-NMR (CDCl₃) Δ (ppm): 9.30-7.20 (m, 16H, Arom.H), 6.035 (s, 1H, Bud-4), 5.966 (t, 1H, J = 9.9 Hz, H-3), 5.618 (t, 1H, J = 9.9 Hz, H-4), 5.580 (dd, 1H, J = 8.1, 9.9 Hz, H-2), 5.290. (D, 1H, J = 8.1 Hz, H-1), 4.232 (m, 1H, H-5), 1.534 (s, 3H, Bud-19), 1.039 (s, 3H, Bud-18), 0.790 (t, 3H, J = 7.3 Hz, Bud-25).
FAB⁺  Ms Calcd. C₅₅H₅₆N₄O₁₅(1012.3), m / z: 1013 (M + H)⁺.
<Example 8-1>23R  →8R
Compound23R(73 mg, 0.12 mmol) was dissolved in pyridine (5 mL), 2-thiophenecarbonyl chloride (79 μL, 0.741 mmol) was added, and the mixture was stirred at room temperature for 1 day, and then 2-thiophenecarbonyl chloride (79 μL, 0.74 mmol) was added. The mixture was further stirred at room temperature for 1 day. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel columnography (toluene: ethyl acetate = 3: 1)8R(92 mg, 72%) was obtained.
Rf = 0.72 (toluene: ethyl acetate = 1: 1)
¹H-NMR (CDCl₃) Δ (ppm): 6.299 (dd, 1H, J = 1.8, 10.3 Hz, Bud-2), 6.077 (s, 1H, Bud-4), 5.772 (t, 1H, J = 9.5 Hz, H-3), 5.554 (t, 1H, J = 9.5 Hz, H-4), 5.448 (dd, 1H, J = 8.1, 9.6 Hz, H− 2), 4.992 (d, 1H, J = 8.1 Hz, H-1), 4.851 (d, 1H, J = 5.9 Hz, Bud-22), 4.702 (d, 1H, J = 18.3 Hz, Bud-21), 4.642 (dd, 1H, J = 3.0, 12.5 Hz, H-6), 4.562 (d, 1H, J = 18.3 Hz, Bud-21) '), 4.436 (dd, 1H, J = 5.1, 12.1 Hz, H-6'), 4.078 (m, 1H, H-5), 1.383 (s, 3H, Bu d-19), 0.911 (t, 3H, J = 7.3 Hz, Bud-25), 0.574 (s, 3H, Bud-18).
FAB⁺  MS Calcd. C₅₁H₅₂O₁₅S₄(1032.1), m / z: (M-17)⁺  1015.
<Example 8-2>23S  →8S
Compound 23S(94 mg, 0.16 mmol) was dissolved in pyridine (5 mL), 2-thiophenecarbonyl chloride (102 μL, 0.95 mmol) was added, and the mixture was stirred at room temperature for 1 day, followed by addition of 2-thiophenecarbonyl chloride (102 μL, 0.95 mmol). The mixture was further stirred at room temperature for 1 day. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel columnography (toluene: ethyl acetate = 3: 1)8S(85 mg, 52%) was obtained.
Rf = 0.49 (toluene: ethyl acetate = 2: 1)
¹H-NMR (CDCl₃) [Delta] (ppm): 6.288 (br-dd, 1H, Bud-2), 6.097 (s, 1H, Bud-4), 5.766 (t, 1H, J = 9.5 Hz, H-) 3), 5.543 (t, 1H, J = 9.5 Hz, H-4), 5.447 (br-t, 1H, J = 9.5 Hz, H-2), 5.135 (br-d) , 1H, Bud-22), 4.965 (d, 1H, J = 7.7 Hz, H-1), 4.781 (d, 1H, J = 18.3 Hz, Bud-21), 4.538 ( d, 1H, J = 18.3 Hz, Bud-21), 4.079 (m, 1H, H-5), 1.379 (s, 3H, Bud-19), 0.894 (t, 3H, J = 7.3 Hz, Bud-25), 0.623 (s, 3H, Bud-18).
FAB⁺  MS Calcd. C₅₁H₅₂O₁₅S₄(1032.1), m / z: (M-17)⁺  1015.
<Example 9>D  →9S,9R
D-glucose sugar donorD(1.2 g, 1.94 mmol) and budesonide (556 mg, 1.29 mmol) were dissolved in dichloromethane (5 mL) and stirred with MS4A (3.8 g) at room temperature for 10 minutes under an argon stream. The reaction mixture was cooled to 0 ° C., silver triflate (498 mg, 1.94 mmol) was added, and the mixture was stirred for 3 hr. Further, silver triflate (498 mg, 1.94 mmol) was added and stirred for 16 hours. The reaction solution was diluted with chloroform and washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine. The chloroform layer was distilled off, and the residue was purified through a silica gel column (toluene: ethyl acetate = 3: 1).9S316 mg (25%),9ROf 435 mg (45%).
9S: Rf = 0.45 (toluene: ethyl acetate = 1: 1)
¹H-NMR (CDCl₃) Δ (ppm): 6.292 (dd, 1H, J = 1.8, 9.9 Hz, Bud-2), 6.023 (s, 1H, Bud-4), 5.735 (t, 1H, J = 9.5 Hz, H-3), 5.581 (t, 1H, J = 9.5 Hz, H-4), 5.401 (dd, 1H, J = 8.1, 9.9 Hz, H− 2), 5.140 (d, 1H, J = 8.1 Hz, H-1), 3.987 (m, 1H, H-5), 1.498 (s, 3H, Bud-19),. 979 (s, 3H, Bud-18), 0.880 (t, 3H, J = 7.3 Hz, Bud-25) FAB⁺  MS Calcd. C₅₁H₅₂O₁₉(968.3), m / z: (M + H)⁺  969, (M + Na)⁺  991.
9R: Rf = 0.48 (toluene: ethyl acetate = 1: 1)
¹H-NMR (CDCl₃) Δ (ppm): 6.301 (dd, 1H, J = 1.8, 9.9 Hz, Bud-2), 6.032 (s, 1H, Bud-4), 5.739 (t, 1H, J = 9.5 Hz, H-3), 5.595 (t, 1H, J = 9.5 Hz, H-4), 5.392 (dd, 1H, J = 8.1, 9.9 Hz, H−) 2), 5.157 (d, 1H, J = 8.1 Hz, H-1), 3.984 (m, 1H, H-5), 1.500 (s, 3H, Bud-19), 0. 943 (s, 3H, Bud-18), 0.910 (t, 3H, J = 7.3 Hz, Bud-25) FAB⁺  MS Calcd. C₅₁H₅₂O₁₉(968.3), m / z: (M + H)⁺  969, (M + Na)⁺  991.
<Example 10>E  →10
D-galactose sugar donorE(340 mg, 0.55 mmol) and budesonide (215 mg, 0.5 mmol) were dissolved in dichloromethane (8 mL) and stirred with MS4A (1 g) at room temperature for 10 minutes under an argon stream. Silver triflate (200 mg, 0.78 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours.C(124 mg, 0.20 mmol) of dichloromethane (2 mL) was added, and the mixture was further stirred at room temperature for 12 hours. The reaction solution was neutralized with triethylamine and filtered through celite. The filtrate was diluted with chloroform and washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over magnesium sulfate, the solvent was distilled off, and the residue was purified through a silica gel column (toluene: ethyl acetate = 3: 1).10Of 232 mg (48%).
Rf = 0.26 (toluene: ethyl acetate = 3: 1)
¹H-NMR (CDCl₃) (Ppm): 7.67 to 6.47 (m, 13H, Arom. H and Bud-1), 6.286 (dd, 0.5H, J = 1.8, 5.5 Hz, Bud-2S) or Bud-2R), 6.266 (dd, 0.5H, J = 1.8, 5.5 Hz, Bud-2R or Bud-2S), 6.028 (br-s, 1H, Bud-4) 55 .825 (d, 0.5H, J = 3.7 Hz, H-4S or H-4R), 5.818 (d, 0.5H, J = 3.7 Hz, H-4R or H-4S), 5 .656 (dd, 1H, J = 8.1, 10.3 Hz, H-2), 5.499 (dd, 0.5H, J = 2.9, 10.3 Hz, H-3R or H-3S) 5.493 (dd, 0.5H, J = 2.9, 10.3 Hz, H-3S or H-3R), 5.15. (T, 0.5H, J = 5.1 Hz, Bud-22S), 5.121 (d, 0.5H, J = 7.0 Hz, Bud-16R), 4.949 (d, 0.5H, J = 7.7 Hz, H-1R or H-1S), 4.935 (d, 0.5 H, J = 7.7 Hz, H-1S or H-1R), 4.461 (m, 1H, Bud-11) ), 1.497 (s, 3H, Bud-19)
FAB⁺  Ms Calcd. C₅₁H₅₂O₁₉(968.3), m / z: (M + H)⁺  969 (M + Na)⁺  991.
<Example 11>10  →11
Compound10(252 mg, 0.24 mmol) was dissolved in methanol: tetrahydrofuran = 1: 1 solution (4 mL), 1N aqueous sodium hydroxide solution (0.2 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction solution was neutralized with Amberlyst 15E, and the resin was removed by filtration. The residue obtained by concentrating the filtrate was purified by Sephadex LH-20 column (MeOH), and further purified by silica gel column (chloroform: methanol = 10: 1) to obtain 95 mg (68%) of a tetraol form. A mixture of this tetraol form (83 mg, 0.14 mmol), pyridine (4 mL), isobutyryl chloride (300 mL, 2.86 mmol) and a catalytic amount of 4-dimethylaminopyridine was stirred at room temperature overnight. The reaction solution was quenched with methanol (4 mL), diluted with chloroform, and washed successively with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated brine. The organic layer was dried over magnesium sulfate, the solvent was distilled off, and the residue was purified through a silica gel column (toluene: ethyl acetate = 4: 1).11Of 74 mg (61%).
Rf = 0.25 (toluene: ethyl acetate = 5: 1)
¹H-NMR (CDCl₃) Δ (ppm): 6.287 (dd, 0.5H, J = 1.8, 4.8 Hz, Bud-2S or Bud-2R), 6.268 (dd, 0.5H, J = 1.8) , 5.5 Hz, Bud-2R or Bud-2S), 6.031 (br-s, 1H, Bud-4), 5.412 (d, 0.5 H, J = 3.3 Hz, H-4S or H -4R), 5.403 (d, 0.5H, J = 3.7Hz, H-4R or H-4S), 5.279 (t, 0.5H, J = 9.9Hz, H-2S or H -2R), 5.277 (t, 0.5H, J = 9.9 Hz, H-2R or H-2S), 5.17-5.11 (m, 2H, H1 and H3), 4.850 ( d, 0.5H, J = 4.8 Hz, Bud-16S), 2.80-2.40 (m, 4H, 4X CH(Me)₂), 1.477 (s, 3H, Bud-19), 0.978 (s, 1.5H, Bud-18S)
FAB⁺  MS Calcd. C₄₇H₆₈O₁₅(872.4), m / z: (M + H)⁺  873 (M + Na)⁺  895.
<Example 12>29  →12
Compound29(223 mg, 0.21 mmol) was dissolved in a mixed solvent of methanol and tetrahydrofuran (1: 1, 15 mL), 5 equivalent of 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 18 hours, and then the reaction mixture was concentrated under reduced pressure. . The residue was purified with Sephadex LH-20 (methanol) to obtain a tetraol form (123 mg, 99%). This tetraol compound (76 mg, 0.13 mmol) was dissolved in pyridine (5 mL), 2-furoyl chloride (33.4 mg, 2.56 mmol) and a catalytic amount of 4-dimethylaminopyridine were added, and the mixture was stirred at room temperature for 42 hours. Stir. Methanol was added to the reaction solution, stirred for 30 minutes and then dried under reduced pressure. The residue was purified by silica gel column chromatography (75 g, toluene / ethyl acetate, 2: 1) and then by Sephadex LH-20 (methanol).12(57 mg, 50%) was obtained.
Rf = 0.19 (toluene: ethyl acetate = 3: 1)
¹H-NMR (CDCl₃) (Ppm): 7.65-6.40 (m, 12H, Arom. H), 6.033 (s, 0.5H, Bud-4S or Bud-4R), 6.023 (s, 0.0. 5H, Bud-4R or Bud-4S), 5.944 (t, 0.5H, J = 10.3 Hz, H-4Sor-4R), 5.916 (t, 0.5H, J = 9.9 Hz, H-4R or H-4S), 5.845 (dd, 1H, J = 3.3, 10.3 Hz, H-3), 5.683 (m, 1H, H-2), 1.485 (s) , 3H, Bud-19), 1.108 (s, 1.5H, Bud-18S or Bud-18R), 1.020 (s, 1.5H, Bud-18R or Bud-18S), 0.928 ( t, 3H, J = 7.3 Hz, Bud-25).
<Example 13>29  →13
The tetraol compound (77 mg, 0.13 mmol) synthesized in Example 12 was dissolved in pyridine (5 mL), isobutyryl chloride (292 μL, 2.80 mmol) and a catalytic amount of 4-dimethylaminopyridine were added, and at room temperature. Stir for 42 hours. Methanol was added to the reaction solution, stirred for 30 minutes and then dried under reduced pressure. The residue was purified by silica gel column chromatography (75 g, toluene / ethyl acetate, 3: 1) and then Sephadex LH-20 (methanol) to give a compound.13(44 mg, 39%) was obtained.
Rf = 0.37 (toluene: ethyl acetate = 3: 1)
¹H-NMR (CDCl₃) Δ (ppm): 6.031 (s, 0.5H, Bud-4S or Bud-4R), 6.022 (s, 0.5H, Bud-4R or Bud-4S), 5.434 (m, 3H, H-4, H-3, H-2), 2.70-2.40 (m, 4H, 4 × CH(CH₃)₂), 1.468 (s, 3H, Bud-19), 1.255-1.080 (m, 24H, i-Bu), 1.040 (s, 1.5H, Bud-18S or Bud-18R) , 0.956 (s, 1.5H, Bud-18R or Bud-18S), 0.927 (t, 1.5H, J = 7.3 Hz, Bud-25S or Bud-25R), 0.919 (t 1.5H, J = 7.3 Hz, Bud-25R or Bud-25S).
FAB⁺  MS Calcd. C₅₁H₇₆O₁₅(928.4), m / z: 951 (M + Na)⁺.
<Example 14>31  →14
Compound31(460 mg, 0.48 mmol) was dissolved in methanol: tetrahydrofuran = 1: 1 solution (10 mL), 1N aqueous sodium hydroxide solution (1.0 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction solution was neutralized with Amberlyst 15E, and the resin was removed by filtration. The residue obtained by concentrating the filtrate was purified by Sephadex LH-20 column (methanol) and further purified by silica gel column (chloroform: methanol = 10: 1) to obtain 275 mg (99%) of a triol form. A mixture of this triol form (130 mg, 0.23 mmol), pyridine (4 mL), 2-furoyl chloride (333 μL, 3.38 mmol) and a catalytic amount of 4-dimethylaminopyridine was stirred overnight at room temperature. The reaction solution was quenched with methanol (4 mL), diluted with chloroform, and washed successively with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated brine. The organic layer was dried over magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column (toluene: ethyl acetate = 5: 3).14144 mg (74%) was obtained.
Rf = 0.39 (toluene: ethyl acetate = 5: 3)
¹H-NMR (CDCl₃) Δ (ppm): 7.72 to 6.27 (m, 10H, Arom.H and Bud-1), 6.385 (m, 1H, Bud-2), 6.033 (br-s, 1H, Bud-4) 55.725 (m, 2H, H-2 and H-3), 5.503 (t, 1H, J = 9.9 Hz, H-4), 5.189 (d, 0.5H, J = 5.1 Hz, Bud-22S), 4.992 (br-s, 1H, H-1), 4.901 (d, 0.5H, J = 5.1 Hz, Bud-22R), 1.470. (S, 3H, Bud-19), 1.333 (d, 3H, J = 6.2 Hz, H-6)
FAB⁺  MS Calcd. C₄₆H₅₀O₁₆(858.3), m / z: (M + H)⁺  859 (M + Na)⁺  881.
<Example 15>31  →15
A mixture of the triol compound synthesized in Example 14 (145 mg, 0.25 mmol), pyridine (5 mL), isobutyryl chloride (400 μL, 3.82 mmol), and a catalytic amount of 4-dimethylaminopyridine was stirred overnight at room temperature. . The reaction mixture was quenched with methanol (4 mL), diluted with chloroform, and washed successively with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated brine. The organic layer was dried over magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column (toluene: ethyl acetate = 5: 4).15144 mg (73%) was obtained.
Rf = 0.64 (toluene: ethyl acetate = 5: 4)
¹H-NMR (CDCl₃) Δ (ppm): 7.284 (d, 1H, J = 10.2 Hz, Bud-1), 6.070 (m, 1H, Bud-2), 6.023 (br-s, 1H, Bud−) 4), 5.42-5.30 (m, 2H, H-2 and H-3), 5.150 (t, 1H, J = 9.9 Hz, H-4), 4.869 (d, 0 .5H, J = 4.8 Hz, Bud-22R), 4.762 (br-s, 1H, H-1), 4.020 (m, 1H, H-5), 2.70-2.35 ( m, 4H, 4 x CH(Me)₂, 1.463 (s, 1.5H, Bud-19R or Bud-19S), 1.659 (s, 1.5H, Bud-19S or Bud-19R)
FAB⁺  MS Calcd. C₄₃H₆₂O₁₃(786.4), m / z: (M + H)⁺  787 (M + Na)⁺  809.
<Example 16>K  →16
Sugar donorK(377 mg, 0.74 mmol) and budesonide (245 mg, 0.57 mmol) were dissolved in dichloromethane (10 mL) and stirred with MS4A (1 g) at room temperature for 10 minutes under an argon stream. Silver triflate (234 mg, 0.91 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 12 hours. The reaction solution was neutralized with triethylamine and filtered through celite. The filtrate was diluted with chloroform and washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column (toluene: ethyl acetate = 2: 1).16Of 251 mg (52%).
Rf = 0.32 (toluene: ethyl acetate = 5: 3)
¹H-NMR (CDCl₃) (Ppm): 7.66 to 6.27 (m, 10H, Arom.H + Bud-1), 6.285 (dd, 0.5H, J = 1.8, 4.8 Hz, Bud-2S or Bud-2R), 6.277 (dd, 0.5H, J = 1.8, 4.8 Hz, Bud-2R or Bud-2S), 6.030 (br-s, 0.5H, Bud-4S or Bud-4R), 6.019 (br-s, 0.5H, Bud-4R or Bud-4S), 5.591 (d, 1H, J = 3.3 Hz, H-4), 5.491 (dd , 1H, J = 3.3 Hz, 8.1 Hz, H-3), 5.180 (t, 0.5H, J = 5.1 Hz, Bud-22S), 4.925 (d, 0.5H, J = 8.1 Hz, H-1S or H-1R), 4.915 (d, 0.5 H, J = 8.1 Hz, -1R or H-1S), 4.859 (d, 0.5H, J = 5.1 Hz, Bud-22R), 4.018 (m, 1H, H-5), 1.259 (s, 1. 5H, Bud-19S or 19R), 1.446 (s, 1.5H, Bud-19R or 19S), 1.414 (d, 3H, J = 7.3 Hz, H-6)
FAB⁺  MS Calcd. C₄₆H₅₀O₁₆(858.3), m / z: (M + H)⁺  859 (M + Na)⁺  881.
<Example 17>16  →17
Compound16(185 mg, 0.19 mmol) was dissolved in methanol: tetrahydrofuran = 1: 1 solution (4 mL), 1N aqueous sodium hydroxide solution (0.4 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction solution was neutralized with Amberlyst 15E, and the resin was removed by filtration. The residue obtained by concentrating the filtrate was purified by Sephadex LH-20 column (methanol) and then purified by silica gel column (chloroform: methanol = 7: 1) to obtain 111 mg (99%) of the triol. A mixture of this triol form (111 mg, 0.19 mmol), pyridine (4 mL), isobutyryl chloride (300 μL, 2.86 mmol) and a catalytic amount of 4-dimethylaminopyridine was stirred overnight at room temperature. The reaction solution was quenched with methanol (4 mL), diluted with chloroform, and washed successively with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated brine. The organic layer was dried over magnesium sulfate, the solvent was distilled off, and the residue was purified through a silica gel column (toluene: ethyl acetate = 4: 1).17Of 100 mg (66%).
¹H-NMR (CDCl₃) Δ (ppm): 6.295 (dd, 0.5H, J = 1.8, 5.5 Hz, Bud-2S or Bud-2R), 6.279 (dd, 0.5H, J = 1.8) , 5.5 Hz, Bud-2R or Bud-2S), 6.035 (Br-s, 1H, Bud-4), 5.300 (dd, 0.5 H, J = 8.1, 10.3 Hz, H -2S or H-2R), 5.280 (dd, 0.5H, J = 8.1, 10.3 Hz, H-2R or H-2S), 5.252 (d, 1H, J = 3.6 Hz) , H-4), 5.094 (dd, 1H, J = 3.6, 10.3 Hz, H-3), 4.882 (d, 0.5H, J = 4.8 Hz, Bud-22R), 4.658 (d, 0.5H, J = 8.1 Hz, H-1R or H-1S), 4.629 (d, 0.5H, J = 8.1) z, H-1S or H-1R), 3.841 (m, H, H-5), 2.80~2.35 (m, 4H, 4x CH(Me)₂), 1.459 (s, 1.5H, Bud-19S or 19R), 1.451 (s, 1.5H, Bud-19R or 19S)
FAB⁺  MS Calcd. C₄₃H₆₂O₁₃(786.4), m / z: (M + H)⁺  787 (M + Na)⁺  809.
<Example 18>L  →18
D-Lactose sugar donorL(1.07 g, 1.0 mmol) and budesonide (430 mg, 1.0 mmol) were dissolved in dichloromethane (20 mL), and stirred with MS4A (1 g) at room temperature for 10 minutes in an argon stream. Silver triflate (385 mg, 1.50 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 12 hours. The reaction solution was neutralized with triethylamine and filtered through celite. The filtrate was diluted with chloroform and washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over magnesium sulfate, the solvent was distilled off, and the residue was purified through a silica gel column (chloroform: methanol = 60: 1).18R177 mg (13%),18S150 mg (11%),18RWhen18SOf 482 mg (34%).
18R: Rf = 0.30 (chloroform: methanol = 60: 1)
¹H-NMR (CDCl₃) Δ (ppm): 7.72 to 6.39 (m, 22H, Arom.H + Bud-1), 6.313 (d, 1H, J = 9.9 Hz, Bud-2), 6.032 (br) -S, 1H, Bud-4), 5.672 (d, 1H, J = 3.3 Hz, H-4b), 5.653 (t, 1H, J = 9.2 Hz, H-3a), 5. 531 (dd, 1H, J = 8.1, 9.9 Hz, H-2b), 5.381 (dd, 1H, J = 3.3, 10.3 Hz, H-3b), 5.269 (t, 1H, J = 9.5 Hz, H-2a), 5.155 (d, 1H, J = 7.7 Hz, H-1a), 4.977 (d, 1H, J = 7.7 Hz, H-1b) 4.852 (d, 1H, J = 4.8 Hz, Bud-22R), 4.209 (t, 1H, J = 9.5 Hz, H-4a), 4.096 (dd 1H, J = 4.7 Hz, 11.0 Hz, H-6b), 3.963 (t, 1H, J = 4.7 Hz, H-5b), 1.492 (s, 3H, Bud-19), 0 .886 (t, 3H, J = 7.3 Hz, -CH₂CH₂ Me), 0.869 (s, 3H, Bud-18)
FAB⁺  MS Calcd. C₇₂H₆₈O₃₀(1412.3), m / z: (M + H)⁺  1413.
18S  Rf = 0.24 (chloroform: methanol = 60: 1)
¹H-NMR (CDCl₃) Δ (ppm): 7.72 to 6.35 (m, 22H, Arom.H + Bud-1), 6.312 (d, 1H, J = 10.3 Hz, Bud-2), 6.025 (br -S, 1H, Bud-4), 5.675 (d, 1H, J = 3.3 Hz, H-4b), 5.656 (t, 1H, J = 9.5 Hz, H-3a), 5. 525 (dd, 1H, J = 8.1, 9.9 Hz, H-2b), 5.368 (dd, 1H, J = 3.3, 10.3 Hz, H-3b), 5.285 (t, 1H, J = 9.3 Hz, H-2a), 5.146 (d, 1H, J = 7.7 Hz, H-1a), 5.122 (br-t, 1H, J = 4.8 Hz, Bud- 22S), 4.963 (d, 1H, J = 7.7 Hz, H-1b), 4.648 (d, 1H, J = 18.7 Hz, Bud-21), 4 491 (d, 1H, J = 18.7 Hz, Bud-21 ′), 4.209 (t, 1H, J = 9.5 Hz, H-4a), 4.080 (dd, 1H, J = 7.0 Hz) , 11.0 Hz, H-6b), 3.958 (t, 1H, J = 7.0 Hz, H-5b), 1.487 (s, 3H, Bud-19), 0.900 (s, 3H, Bud-18), 0.852 (t, 3H, J = 7.3 Hz, -CH₂CH₂ Me),
FAB⁺  MS Calcd. C₇₂H₆₈O₃₀(1412.3), m / z: (M + H)⁺  1413 (M + Na)⁺  1435.
<Example 19-1>18R  →19R
Compound18R(124 mg, 88 μmol) was dissolved in methanol: tetrahydrofuran = 1: 1 solution (5 mL), 1N-aqueous sodium hydroxide solution (0.5 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction solution was neutralized with Amberlyst 15E, and the resin was removed by filtration. The residue obtained by concentrating the filtrate was purified by Sephadex LH-20 column (MeOH) to obtain 66 mg (99%) of Lac-Free-BD (R). A mixture of the Lac-Free-BD (R) (66 mg, 88 μmol), pyridine (4 mL), isobutyryl chloride (335 μL, 3.19 mmol), and a catalytic amount of 4-dimethylaminopyridine was stirred at room temperature overnight. The reaction solution was quenched with methanol (4 mL), diluted with chloroform, and washed successively with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated brine. The organic layer was dried over magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column (toluene: ethyl acetate = 2: 1).19ROf 61 mg (54%).
Rf = 0.36 (toluene: ethyl acetate = 2: 1)
¹H-NMR (CDCl₃) Δ (ppm): 7.328 (d, 1H, J = 9.9 Hz, Bud-1), 6.303 (d, 1H, J = 9.9 Hz, Bud-2), 6.032 (br−) s, 1H, Bud-4), 5.378 (d, 1H, J = 2.9 Hz, H-4b), 5.261 (t, 1H, J = 9.5 Hz, H-3a), 5.129. (Dd, 1H, J = 7.7, 10.6 Hz, H-2b), 5.015 (dd, 1H, J = 3.3, 10.3 Hz, H-3b), 4.983 (d, 1H , J = 8.1 Hz, H-1a), 4.906 (d, 1H, J = 7.7 Hz, H-1b), 3.933 (t, 1H, J = 4.7 Hz, H-5b), 3.851 (t, 1H, J = 9.9 Hz, H-4a), 2.70-2.30 (m, 4H, 4 × CH(Me)₂), 1.482 (s, 3H, Bud-19), 1.25 to 1.05 (m, 42H, 14 x Me), 0.909 (t, 3H, J = 7.3 Hz, -CH CH₂ Me)
FAB⁺  Ms Calcd. C₆₅H₉₆O₂₃(1244.5), m / z: (M + H)⁺  1245.
<Example 19-2>18S  →19S
Compound18S(169 mg, 0.12 mmol) was dissolved in methanol: tetrahydrofuran = 1: 1 solution (5 mL), 1N-aqueous sodium hydroxide solution (0.5 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction solution was neutralized with Amberlyst 15E, and the resin was removed by filtration. The residue obtained by concentrating the filtrate was purified by Sephadex LH-20 column (methanol) to obtain 70 mg (78%) of Lac-Free-BD (S). A mixture of the Lac-Free-BD (S) (70 mg, 92 μmol), pyridine (4 mL), isobutyryl chloride (335 mL, 3.19 mmol) and a catalytic amount of 4-dimethylaminopyridine was stirred at room temperature overnight. The reaction solution was quenched with methanol (4 mL), diluted with chloroform, and washed successively with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated brine. The organic layer was dried over magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column (toluene: ethyl acetate = 2: 1).19SOf 65 mg (56%).
Rf = 0.36 (toluene: ethyl acetate = 2: 1)
¹H-NMR (CDCl₃) Δ (ppm): 7.328 (d, 1H, J = 9.9 Hz, Bud-1), 6.301 (d, 1H, J = 9.9 Hz, Bud-2), 6.028 (br−) s, 1H, Bud-4), 5.377 (d, 1H, J = 3.0 Hz, H-4b), 5.265 (t, 1H, J = 9.5 Hz, H-3a), 5.129. (Dd, 1H, J = 8.0, 10.3 Hz, H-2b), 5.012 (dd, 1H, J = 3.3, 10.3 Hz, H-3b), 4.978 (d, 1H , J = 8.1 Hz, H-1a), 4.915 (d, 1H, J = 7.7 Hz, H-1b), 4.638 (d, 1H, J = 18.7 Hz, Bud-21), 4.514 (d, 1H, J = 18.7 Hz, Bud-21 ′), 4.072 (dd, 1H, J = 7.0, 11.0 Hz, H-6b), 3. 930 (t, 1H, J = 4.7 Hz, H-5b), 3.839 (t, 1H, J = 9.9 Hz, H-4a), 3.516 (t, 1H, J = 7.0, 9.9 Hz, H-5a), 2.70-2.30 (m, 4H, 4 × C)H(Me)₂), 1.475 (s, 3H, Bud-19), 1.25 to 1.05 (m, 42H, 14XMe), 0.908 (s, 3H, Bud-18), 0.880 (t, 3H) , J = 7.3 Hz, -CH CH₂ MeFAB⁺  MS Calcd. C₆₅H₉₆O₂₃(1244.5), m / z: (M + H)⁺  1245 (M + Na)⁺  1267.
<Example 20>A  →21S,21R
D-glucose sugar donorA(1.2 g, 1.82 mmol) and budesonide (521 mg, 1.21 mmol) were dissolved in dichloromethane (5 mL) and stirred with MS4A (3.8 g) at room temperature for 10 minutes under an argon stream. The reaction mixture was cooled to 0 ° C., silver triflate (467 mg, 1.82 mmol) was added, and the mixture was stirred for 3 hr. Further, silver triflate (233 mg, 0.91 mmol) was added and stirred for 16 hours. The reaction solution was diluted with chloroform and washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine. The chloroform layer was distilled off, and the residue was purified through a silica gel column (toluene: ethyl acetate = 5: 1).21S424 mg (41%),21ROf 450 mg (44%) was obtained.
21S: Rf = 0.36 (toluene: ethyl acetate = 3: 1)
¹H-NMR (CDCl₃) Δ (ppm): 6.291 (dd, 1H, J = 1.8, 9.9 Hz, Bud-2), 6.022 (s, 1H, Bud-4), 5.907 (t, 1H, J = 9.5 Hz H-3), 5.733 (t, 1H, J = 9.5 Hz, H-4), 5.542 (dd, 1H, J = 8.1, 9.9 Hz, H-2) ), 5.205 (d, 1H, J = 8.1 Hz, H-1), 4.051 (m, 1H, H-5), 1.494 (s, 3H, Bud-19), 1.009. (S, 3H, Bud-18), 0.872 (t, 3H, J = 7.3 Hz, Bud-25) FAB⁺  MS Calcd. C₆₃H₆₈O₁₅(1064.4), m / z: (M + Na)⁺  1087.
21R: Rf = 0.39 (toluene: ethyl acetate = 3: 1)
¹H-NMR (CDCl₃) Δ (ppm): 6.303 (dd, 1H, J = 1.8, 9.9 Hz, Bud-2), 6.031 (s, 1H, Bud-4), 5.907 (t, 1H, J = 9.5 Hz, H-3), 5.749 (t, 1H, J = 9.5 Hz, H-4), 5.527 (dd, 1H, J = 8.1, 9.9 Hz, H− 2), 5.227 (d, 1H, J = 8.1 Hz, H-1), 4.026 (m, 1H, H-5), 1.494 (s, 3H, Bud-19), 0. 979 (s, 3H, Bud-18), 0.880 (t, 3H, J = 7.3 Hz, Bud-25) FAB⁺  MS Calcd. C₅₉H₆₀O₁₅(1008.4), m / z: (M + H)⁺  1009, (M + Na)⁺  1031.
<Example 21>B  →22S,22R
D-glucose sugar donorB(15.2 g, 23.1 mmol) and budesonide (6.0 g, 13.9 mmol) were dissolved in dichloromethane (10 mL), and stirred with MS4A (38 g) at room temperature for 10 minutes under an argon stream. The reaction mixture was cooled to 0 ° C., silver triflate (5.37 g, 20.9 mmol) was added, and the mixture was stirred for 16 hr. The reaction solution was diluted with chloroform and washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine. The chloroform layer was distilled off, and the residue was purified through a silica gel column (toluene: ethyl acetate = 6: 1).22S6.1 g (41%),22R6.35 g (43%) was obtained.
22S: Rf = 0.33 (toluene: ethyl acetate = 5: 1)
¹H-NMR (CDCl₃) Δ (ppm): 6.286 (dd, 1H, J = 1.8, 9.9 Hz, Bud-2), 6.020 (s, 1H, Bud-4), 5.866 (t, 1H, J = 9.5 Hz, H-3), 5.680 (t, 1H, J = 9.5 Hz, H-4), 5.506 (dd, 1H, J = 8.1, 9.9 Hz, H− 2), 5.159 (d, 1H, J = 8.1 Hz, H-1), 4.025 (m, 1H, H-5), 2.395, 2.355, 2.300 (3s, 12H) , CH₃), 1.490 (s, 3H, Bud-19), 0.992 (s, 3H, Bud-18), 0.872 (t, 3H, J = 7.3 Hz, Bud-25)
FAB⁺  MS Calcd. C₅₉H₆₀O₁₅(1008.4), m / z: (M + H)⁺  1009, (M + Na)⁺  1031.
22R  : Rf = 0.36 (toluene: ethyl acetate = 5: 1)
¹H-NMR (CDCl₃) Δ (ppm): 6.299 (dd, 1H, J = 1.8, 9.9 Hz, Bud-2), 6.029 (s, 1H, Bud-4), 5.867 (t, 1H, J = 9.5 Hz, H-3), 5.694 (t, 1H, J = 9.5 Hz, H-4), 5.491 (dd, 1H, J = 8.1, 9.9 Hz, H− 2), 5.179 (d, 1H, J = 8.1 Hz, H-1), 4.001 (m, 1H, H-5), 2.413, 2.363, 2.355, 2.298 (4s, 12H, CH₃), 1.491 (s, 3H, Bud-19), 0.957 (s, 3H, Bud-18), 0.901 (t, 3H, J = 7.3 Hz, Bud-25) FAB⁺  MS Calcd. C₅₉H₆₀O₁₅(1008.4), m / z: (M + Na)⁺  1031.
<Example 22-1>22S  →23S
Compound22S(1.13 g, 1.06 mmol) was dissolved in methanol: tetrahydrofuran = 1: 1 solution (10 mL), 1N aqueous sodium hydroxide solution (0.5 mL) was added, and the mixture was stirred at room temperature for 3 hr. After neutralizing the reaction solution with Amberlyst 15E, the reaction solution was purified as it was with an LH-20 column (chloroform: methanol = 1: 2). Further silica gel column purification (chloroform: methanol = 10: 1)23SOf 629 mg (99%).
Rf = 0.44 (chloroform: methanol = 5: 1)
¹H-NMR (CD₃OD) δ (ppm): 7.450 (d, 1H, J = 10.3 Hz, Bud-1), 6.251 (dd, 1H, J = 1.8, 9.9 Hz, Bud-2), 6 .008 (s, 1H, Bud-4), 5.199 (t, 1H, J = 4.9 Hz, Bud-22), 4.407 (m, 1H, Bud-11), 4.317 (d, 1H, J = 7.7 Hz, H-1), 1.486 (s, 3H, Bud-19), 0.990 (s, 3H, Bud-18), 0.916 (t, 3H, J = 7 .3Hz, Bud-25)
<Example 22-2>22R  →23R
Compound22R(5.0 g, 4.69 mmol) was dissolved in 15 ml of methanol: tetrahydrofuran = 1: 1 solution, 1N aqueous sodium hydroxide solution (0.8 ml) was added, and the mixture was stirred at room temperature for 3 hours. After neutralizing the reaction solution with Amberlyst 15E, the reaction solution was purified as it was with an LH-20 column (chloroform: methanol = 1: 2). Further silica gel column purification (chloroform: methanol = 10: 1)23ROf 2.78 g (99%).
Rf = 0.48 (chloroform: methanol = 5: 1)
¹H-NMR (CD₃OD) δ (ppm): 7.450 (d, 1H, J = 10.3 Hz, Bud-1), 6.257 (dd, 1H, J = 1.8, 9.9 Hz, Bud-2), 6 .015 (s, 1H, Bud-4), 4.618 (t, 1H, J = 4.4 Hz, Bud-22), 4.424 (m, 1H, Bud-11), 4.327 (d, 1H, J = 7.7 Hz, H-1), 1.489 (s, 3H, Bud-19), 0.943 (s, 3H, Bud-18), 0.928 (t, 3H, J = 7 .3Hz, Bud-25)
<Example 23-1>23R  →24R
Compound3R(100 mg, 0.17 mmol) was dissolved in pyridine (20 mL), 4-methoxybenzoyl chloride (304 mg, 1.78 mmol) and a catalytic amount of 4-dimethylaminopyridine were added, and the mixture was stirred at room temperature for 18 hours. Methanol was added to the reaction solution, stirred for 30 minutes and then dried under reduced pressure. The residue was purified by silica gel column chromatography (200 g, toluene / ethyl acetate, 2: 1) and then by Sephadex LH-20 (methanol).24R(88 mg, 46%) was obtained.
Rf = 0.21 (toluene: ethyl acetate = 4: 1)
¹H-NMR (CDCl₃) Δ (ppm): 7.975-7.789 (4dd, 8H, Ph), 6.868-6.755 (4dd, 8H, Ph), 6.029 (s, 1H, Bud-4), 5 .826 (t, 1H, J = 9.9 Hz, H-3), 5.667 (t, 1H, J = 9.9 Hz, H-4), 5.466 (dd, 1H, J = 8.1) , 9.9 Hz, H-2), 5.157 (d, 1H, J = 8.1 Hz, H-1), 3.979 (m, 1H, H-5), 1.494 (s, 3H, Bud-19), 0.964 (s, 3H, Bud-18), 0.902 (t, 3H, J = 7.7 Hz, Bud-25).
<Example 23-2>23S  →24S
Compound23S(100 mg, 0.17 mmol) was dissolved in pyridine (20 mL), 4-methoxybenzoyl chloride (304 mg, 1.78 mmol) and a catalytic amount of 4-dimethylaminopyridine were added, and the mixture was stirred at room temperature for 18 hours. Methanol was added to the reaction solution, stirred for 30 minutes and then dried under reduced pressure. The residue was purified by silica gel column chromatography (200 g, toluene / ethyl acetate, 3: 1) and then Sephadex LH-20 (methanol) to give a compound.24S(87 mg, 46%) was obtained.
Rf = 0.24 (toluene: ethyl acetate = 4: 1)
¹H-NMR (CDCl₃) Δ (ppm): 7.974-7.788 (4dd, 8H, Arom.H), 6.863-6.753 (4dd, 8H, Arom.H), 6.021 (s, 1H, Bud−) 4), 5.825 (t, 1H, J = 9.5 Hz, H-3), 5.655 (t, 1H, J = 9.5 Hz, H-4), 5.482 (dd, 1H, J = 8.1, 9.5 Hz, H-2), 5.138 (d, 1H, J = 8.1 Hz, H-1), 4.006 (m, 1H, H-5), 1.496 ( s, 3H, Bud-19), 1.003 (s, 3H, Bud-18), 0.875 (t, 3H, J = 7.7 Hz, Bud-25).
<Example 24-1>23S  →25S
Compound23S(72 mg, 0.12 mmol) was dissolved in pyridine (5 mL), 4-propylbenzoyl chloride (122 μL, 0.73 mmol) was added, and the mixture was stirred at room temperature for 1 day, followed by addition of 4-propylbenzoyl chloride (122 μL, 0.73 mmol). The mixture was further stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel columnography (toluene: ethyl acetate = 5: 1),25S(87 mg, 61%) was obtained.
Rf = 0.74 (toluene: ethyl acetate = 2: 1)
¹H-NMR (CDCl₃) Δ (ppm): 6.292 (dd, 1H, J = 1.8, 10.3 Hz, Bud-2), 6.023 (s, 1H, Bud-4), 5.874 (t, 1H, J = 9.5 Hz, H-3), 5.695 (t, 1H, J = 9.5 Hz, H-4), 5.512 (dd, 1H, J = 8.1, 9.5 Hz, H− 2), 5.174 (d, 1H, J = 8.1 Hz, H-1), 5.130 (d, 1H, J = 5.1 Hz, Bud-22), 1.498 (s, 3H, Bud -19), 1.001 (s, 3H, Bud-18).
FAB⁺  MS Calcd. C₇₁H₈₄O₁₅(1176.5), m / z: (M + Na)⁺  1199.
<Example 24-2>23R  →25R
Compound23R(200 mg, 0.34 mmol) was dissolved in pyridine (7 mL), 4-propylbenzoyl chloride (337 μL, 2.0 mmol) was added, and the mixture was stirred at room temperature for 1 day, and 4-propylbenzoyl chloride (337 μL, 2.0 mmol) was added. And stirred at room temperature for 1 day. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel columnography (toluene: ethyl acetate = 5: 1)25R(284 mg, 71%) was obtained.
Rf = 0.65 (toluene: ethyl acetate = 3: 1)
¹H-NMR (CDCl₃) Δ (ppm): 6.309 (dd, 1H, J = 1.8, 10.3 Hz, Bud-2), 6.036 (s, 1H, Bud-4), 5.896 (t, 1H, J = 9.9 Hz, H-3), 5.731 (t, 1H, J = 9.9 Hz, H-4), 5.519 (dd, 1H, J = 7.7, 9.9 Hz, H− 2), 5.206 (d, 1H, J = 7.7 Hz, H-1), 4.806 (d, 1H, J = 4.4 Hz, Bud-22), 4.817 (dd, 1H, J = 4.4, 12.1 Hz, H-6), 4.751 (d, 1H, J = 19.1 Hz, Bud-21), 4.580 (d, 1H, J = 19.1 Hz, Bud-21) '), 4.013 (m, 1H, H-5), 1.502 (s, 3H, Bud-19), 0.981 (s, 3H, Bud-18).
FAB⁺  MS Calcd. C₇₁H₈₄O₁₅(1176.5), m / z: (M + Na)⁺  1199.
<Example 25-1>23S  →26S
Compound23S(56 mg, 0.10 mmol) was dissolved in pyridine (5 mL), 2-naphthoyl chloride (145 mg, 0.76 mmol) was added, and the mixture was stirred at room temperature for 1 day. Next, dimethylaminopyridine was added and stirred at room temperature for 1 day, 2-naphthoyl chloride (145 mg, 0.76 mmol) was added, and the mixture was further stirred at room temperature for 1 day. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel columnography (toluene: ethyl acetate = 5: 1),26S(78 mg, 68%) was obtained.
Rf = 0.62 (toluene: ethyl acetate = 2: 1)
¹H-NMR (CDCl₃) Δ (ppm): 6.244 (dd, 1H, J = 1.8, 9.9 Hz, Bud-2), 6.137 (t, 1H, J = 9.5 Hz, H-3), 6. 013 (s, 1H, Bud-4), 5.940 (t, 1H, J = 9.5 Hz, H-4), 5.755 (dd, 1H, J = 8.1, 9.5 Hz, H− 2), 5.297 (d, 1H, J = 8.1 Hz, H-1), 5.136 (d, 1H, J = 5.1 Hz, Bud-22), 4.274 (m, 1H, H) -5), 1.473 (s, 3H, Bud-19), 1.064 (s, 3H, Bud-18), 0.858 (t, 3H, J = 7.3 Hz, Bud-25).
FAB⁺  MS Calcd. C₇₅H₆₈O₁₅(1208.4), m / z: (M + H)⁺  1209, (M + Na)⁺  1231.
<Example 25-2>23R  →26R
Compound23R(80 mg, 0.13 mmol) was dissolved in pyridine (5 mL), 2-naphthoyl chloride (206 mg, 1.08 mmol) was added, and the mixture was stirred at room temperature for 1 day. Next, dimethylaminopyridine was added, and the mixture was stirred at room temperature for 1 day, 2-naphthoyl chloride (206 mg, 1.08 mmol) was added, and the mixture was further stirred at room temperature for 1 day. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel columnography (toluene: ethyl acetate = 4: 1),26R(131 mg, 80%) was obtained.
Rf = 0.63 (toluene: ethyl acetate = 2: 1)
¹H-NMR (CDCl₃) Δ (ppm): 6.257 (dd, 1H, J = 1.8, 9.9 Hz, Bud-2), 6.126 (t, 1H, J = 9.5 Hz, H-3), 6. 024 (s, 1H, Bud-4), 5.934 (t, 1H, J = 9.5 Hz, H-4), 5.726 (dd, 1H, J = 7.7, 9.9 Hz, H- 2), 5.297 (d, 1H, J = 7.7 Hz, H-1), 4.899 (dd, 1H, J = 4.4, 12.1 Hz, H-6), 4.853 (d , 1H, J = 4.4 Hz, Bud-22), 4.839 (d, 1H, J = 18.7 Hz, Bud-21), 4.758 (dd, 1H, J = 3.7, 11.7 Hz) , H-6 ′), 4.645 (d, 1H, J = 18.7 Hz, Bud-21 ′), 4.231 (m, 1H, H-5) 31.476 (s, 3H, Bud 19), 1.010 (s, 3H, Bud-18), 0.894 (t, 3H, J = 7.3Hz, Bud-25).
FAB⁺  MS Calcd. C₇₅H₆₈O₁₅(1208.4), m / z: (M + H)⁺  1209.
<Example 26>C  →27
Molecular sieves 4A (2.5 g), D-glucose sugar donor, dried under reduced pressure in a light-shielded two-diameter Kolben under an argon atmosphereC(414 mg, 0.46 mmol), budesonide (200 mg, 0.46 mmol), silver triflate (150 mg, 0.58 mmol) and chloroform (5 mL) were added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and filtered through celite. The filtrate was washed with saturated aqueous sodium hydrogen carbonate and saturated brine in that order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (300 g, toluene / ethyl acetate, 2: 1) and then Sephadex LH-20 (methanol).27(286 mg, 50%) was obtained.
Rf = 0.31 (toluene: ethyl acetate = 2: 1)
¹H-NMR (CDCl₃): 8.15-7.15 (m, 16H, Arom. H), 6.293, 6.273 (2s, 1H, Bud-4S and Bud-4R), 5.910 (m, 1H, H) -4), 5.237, 5.207 (2d, 1H, J = 7.7 Hz, H-1S and H-1R), 3.92 (m, 12H, COOCH₃), 1.734 (s, 1H, Bud-19), 0.932 (m, 3H, Bud-25).
FAB⁺  MS Calcd. C₆₇H₆₈O₂₃(1240.4), m / z: 1263 (M + Na)⁺.
<Example 27>F  →28
D-galactose sugar donorF(465 mg, 0.65 mmol) and budesonide (215 mg, 0.5 mmol) were dissolved in dichloromethane (8 mL) and stirred with MS4A (1 g) at room temperature for 10 minutes under an argon stream. Silver triflate (200 mg, 0.78 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours.F(72 mg, 0.10 mmol) of dichloromethane (1 mL) was added, and the mixture was further stirred at room temperature for 12 hours. The reaction solution was neutralized with triethylamine and filtered through celite. The filtrate was diluted with chloroform and washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over magnesium sulfate, the solvent was distilled off, and the residue was purified through a silica gel column (toluene: ethyl acetate = 4: 1).28Of 467 mg (88%).
Rf = 0.41 (toluene: ethyl acetate = 4: 1)
¹H-NMR (CDCl₃) Δ (ppm): 6.283 (dd, 0.5H, J = 1.8, 5.5 Hz, Bud-2S or Bud-2R), 6.263 (dd, 0.5H, J = 1.8) , 5.5 Hz, Bud-2R or Bud-2S), 6.031 (Br-s, 1H, Bud-4), 5.935 (d, 0.5 H, J = 3.7 Hz, H-4S or H -4R), 5.925 (d, 0.5H, J = 3.7 Hz, H-4R or H-4S), 5.162 (t, 0.5H, J = 5.1 Hz, Bud-22S), 5.117 (d, 0.5 H, J = 6.6 Hz, Bud-16R), 4.983 (d, 0.5 H, J = 8.1 Hz, H-1R or H-1S), 4.978 ( d, 0.5H, J = 8.1 Hz, H-1S or H-1R), 2.457, 2.411, 2.354, 2.. 294 (4s, 12H, 4XCH3), 1.495 (s, 1.5H, Bud-19R or Bud-19S), 1.492 (s, 1.5H, Bud-19R or Bud-19S)
FAB⁺  MS Calcd. C₆₃H₆₈O₁₅(1064.4), m / z: (M + H)⁺  1065 (M + Na)⁺  1087.
<Example 28>G  →29
Molecular sieves 4A (1.7 g), D-mannose sugar donor, dried under reduced pressure in a light-shielded two-diameter Kolben under an argon atmosphereG(2.30 g, 3.21 mmol), budesonide (1.39 g, 3.22 mmol), silver triflate (0.607 g, 2.36 mmol) and dichloromethane (12 mL) were added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and filtered through celite. The filtrate was washed with saturated aqueous sodium hydrogen carbonate and saturated brine in that order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (300 g, toluene / ethyl acetate, 3: 1, chloroform / ethyl acetate, 9: 1) and then Sephadex LH-20 (methanol).29(792 mg, 23%) was obtained.
Rf = 0.16 (toluene: ethyl acetate = 7: 1)
¹H-NMR (CDCl₃) Δ (ppm): 6.182 (t, 0.5H, J = 10.3 Hz, H-4S or H-4R), 6.131 (t, 0.5H, J = 10.3 Hz, H-4R) or H-4S), 6.036 (br-s, 1H, Bud-4), 5.934 (m, 1H, H-3), 5.740 (m, 1H, H-2), 2.441. , 2.422, 2.412, 2.400, 2.370, 2.362, 2.299 (7s, 12H, Tol-CH₃), 1.497 (s, 1.5H, Bud-19S or Bun-19R), 1.491 (s, 1.5H, Bud-19R or Bun-19S), 1.151 (s, 1.5H, Bud-18S or Bun-18R), 1.050 (s, 1.5H, Bud-18R or Bud-18S), 0.896 (t, 1.5H, J = 7.3 Hz, Bud-25S or Bud- 25R), 0.932 (t, 1.5H, J = 7.7 Hz, Bud-25R or Bud-25S)
FAB⁺  MS Calcd. C₆₃H₆₈O₁₅(1064.4), m / z: 1087 (M + Na)⁺.
<Example 29>H  →30
D-glucuronic acid sugar donorH(1.22 g, 1.95 mmol) and budesonide (646 mg, 1.5 mmol) were dissolved in dichloromethane (25 mL), and stirred with MS4A (5 g) at room temperature for 10 minutes under an argon stream. Silver triflate (578 mg, 2.25 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 12 hours. The reaction solution was neutralized with triethylamine and filtered through celite. The filtrate was diluted with chloroform and washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over magnesium sulfate, the solvent was distilled off, and the residue was purified through a silica gel column (toluene: ethyl acetate = 3: 1).30Of 677 mg (45%).
Rf = 0.30, 0.33 (hexane: ethyl acetate = 5: 3)
¹H-NMR (CDCl₃) Δ (ppm): 6.300 (dd, 1H, J = 1.8, 9.9 Hz, Bud-2), 6.029 (br-s, 1H, Bud-4), 5.898 (t, 1H, J = 9.6 Hz, H-3), 5.641 (t, 1H, J = 9.5 Hz, H-2), 5.540 (dd, 1H, J = 7.7, 9.2 Hz, H-4), 5.215 (d, 1H, J = 7.3 Hz, H-1), 4.863 (d, 1H, J = 4.7 Hz, Bud-22R), 4.310 (d, 1H) , J = 9.9 Hz, H-5), 3.649 (s, 3H, COOMe), 2.433, 2.373, 2.362 (3S, 9H, 3XMe), 1.465 (s, 3H, Bud-19), 0.829 (t, 3H, J = 7.3 Hz, -CH₂CH₂ Me)
FAB⁺  MS Calcd. C₅₆H₆₂O₁₅(974.3), m / z: (M + H)⁺  975 (M + Na)⁺  997
<Example 30>I  →31
L-rhamnose sugar donorI(727 mg, 1.2 mmol) and budesonide (430 mg, 1.0 mmol) were dissolved in dichloromethane (20 mL), and stirred with MS4A (1 g) at room temperature for 10 minutes under an argon stream. Silver triflate (385 mg, 1.50 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 17 hours. The reaction solution was neutralized with triethylamine and filtered through celite. The filtrate was diluted with chloroform and washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over magnesium sulfate, the solvent was distilled off, and the residue was purified through a silica gel column (chloroform: methanol = 60: 1).31Of 707 mg (74%).
Rf = 0.33 (toluene: ethyl acetate = 3: 1)
¹H-NMR (CDCl₃) Δ (ppm): 7.973 (d, 2H, J = 8.1 Hz, Arom.H), 7.868 (d, 2H, J = 8.1 Hz, Arom.H), 7.709 (d, 2H, J = 8.1 Hz, Arom.H), 7.278 (d, 2H, J = 8.1 Hz, Arom.H), 7.184 (d, 2H, J = 8.1 Hz, Arom.H) 7.066 (d, 2H, J = 8.1 Hz, Arom.H), 6.291 (br-d, 0.5H, J = 1.8, Bud-2S or Bud-2R), 6.270. (Br-d, 0.5H, J = 1.8, Bud-2R or Bud-2S), 6.034 (br-s, 1H, Bud-4), 5.82-5.74 (m, 2H , H-2 and H-3), 5.675 (t, 1H, J = 9.9 Hz, H-4), 5.206 (d, 0.5H) J = 5.1 Hz, Bud-22S), 5.043 (br-s, 1H, H-1), 4.923 (d, 0.5H, J = 5.1 Hz, Bud-22R), 2.435. , 2.360, 2.292 (3s, 9H, 3XMe), 1.485 (s, 3H, Bud-19)
FAB⁺  MS Calcd. C₅₅H₆₂O₁₃(930.3), m / z: (M + Na)⁺  953.
<Example 31>J  →32
L-fucose sugar donorJ(394 mg, 0.65 mmol) and budesonide (215 mg, 0.5 mmol) were dissolved in dichloromethane (8 mL) and stirred with MS4A (1 g) at room temperature for 10 minutes under an argon stream. Silver triflate (200 mg, 0.78 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 12 hours. The reaction solution was neutralized with triethylamine and filtered through celite. The filtrate was diluted with chloroform and washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over magnesium sulfate, the solvent was distilled off, and the residue was purified through a silica gel column (toluene: ethyl acetate = 4: 1).12Of 336 mg (70%).
Rf = 0.34 (toluene: ethyl acetate = 4: 1)
¹H-NMR (CDCl₃) Δ (ppm): 8.01 to 7.03 (m, 13H, Arom.H + Bud-1), 6.295 (dd, 0.5H, J = 1.8, 4.8 Hz, Bud-2S or Bud-2R), 6.278 (dd, 0.5H, J = 1.8, 4.8 Hz, Bud-2R or Bud-2S), 6.040 (br-s, 0.5H, Bud-4S or Bud-4R), 6.025 (br-s, 0.5H, Bud-4R or Bud-4S), 5.802 (dd, 0.5H, J = 8.0, 10.7 Hz, H-2R or H-2S), 5.768 (dd, 0.5H, J = 8.0, 10.7 Hz, H-2R or H-2S), 5.681 (d, 1H, J = 3.3 Hz, H- 4), 5.554 (dd, 0.5H, J = 3.3, 8.0 Hz, H-3R or H-3 ), 5.537 (dd, 0.5H, J = 3.3, 8.0 Hz, H-33 or H-3R), 5.198 (t, 0.5H, J = 5.1 Hz, Bud-22S). ), 4.988 (d, 0.5H, J = 8.1 Hz, H-1S or H-1R), 4.983 (d, 0.5H, J = 8.1 Hz, H-1R or H-1S). ), 4.870 (d, 0.5H, J = 5.1 Hz, Bud-22R), 4.078 (m, 1H, H-5), 2.450, 2.354, 2.297, (3S , 9H, 3XMe), 1.469 (s, 1.5H, Bud-19R or 19s), 1.448 (s, 1.5H, Bud-19S or 19R), 1.424 (d, 3H, J = 7.3Hz, H-6)
<Example 32>M  →33
Molecular sieves 4A (1.5 g), D-xylose sugar donor, dried under reduced pressure in a light-shielded two-diameter Kolben under an argon atmosphereM(708 mg, 1.25 mmol), budesonide (538 mg, 1.25 mmol), trimethylsilyl triflate (290 μL, 1.5 mmol) and dichloromethane (10 mL) were added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and filtered through celite. The filtrate was washed with saturated aqueous sodium hydrogen carbonate and saturated brine in that order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (300 g, toluene / ethyl acetate, 4: 1) and then Sephadex LH-20 (methanol)33(206 mg, 20%) was obtained.
Rf = 0.10 (toluene: ethyl acetate = 10: 1)
¹H-NMR (CDCl₃) Δ (ppm): 8.16-7.40 (m, 15H, Arom. H), 6.021 (s, 0.6H, Bud-4S or Bud-4R), 6.012 (s, 0.00). 4H, Bud-4R or Bud-4S), 5.885 (d, 1H, J = 5.5 Hz, H-3), 5.643 (s, 1H, H-2), 5.441 (s, 0 .6H, H-1S or H-1R), 5.432 (s, 0.4H, H-1R or H-1S), 5.011 (m, 1H, H-4), 1.420 (s, 0.6H, Bud-19S or Bud-19R), 1.415 (s, 0.4H, Bud-19R or Bud-19S), 0.961 (s, 0.4H, Bud-18S or Bud-18R) , 0.916 (s, 0.6H, Bud-18R or Bud-18S), 0.8 99, 0.884 (2t, 3H, J = 7.3, 7.7 Hz, Bud-25).
[Croton oil-induced granulomas]
(1) Experimental method
A group of 5 male SD rats weighing 160 to 180 g, each group was shaved with a clipper under ether anesthesia, and 20 ml of air was injected subcutaneously into the back to produce an air sac. The next day, 1 ml of cottonseed oil containing 1% croton oil was administered into the sac. The test drug was suspended in croton oil-containing cottonseed oil and administered. Seven days later, blood was collected under ether anesthesia, and the exudate in the sac was collected and the amount of liquid was measured. In addition, granuloma and thymus formed around the sac were removed and weighed. The exudate weight and thymus weight are shown in Tables 1 and 2 as the inhibition rate (%) relative to the control group. A 30% leachate inhibitory concentration and a 30% thymic atrophy concentration were determined from the least squares regression curve. The results of 30% exudate inhibition concentration and 30% thymus atrophy concentration were ranked according to Table 3, and the sum of the exudate and thymus ranks was shown in Table 4 as the overall rank.
(2) Results
The higher the leachate inhibitory effect (pharmacological activity index), the lower the medicinal rank, and the lower the toxicity rank, the smaller the thymic atrophy (systemic side effect index). That is, a compound having a higher pharmacological effect and fewer systemic side effects is obtained as the value of the overall evaluation rank, which is the sum of the ranks of drug efficacy and toxicity, is lower. The total rank of the existing steroid drugs diflucortron valerate and betamethasone valerate is 8 and budesonide is 7, whereas 21-substituted glycosyl steroid compounds are 6 or less, which is clearly a highly safe compound It was suggested that In addition, the compound para-tol-Glc-DF already applied for international application (international publication number: WO95 / 09177) has an overall rank of 6, and the compound according to the present invention in which steroids are easily metabolized steroids is more effective. It was shown that enhancement and reduction of side effects were made.
From the above, it was found that the compound of the present invention is a safe anti-inflammatory steroid with few systemic side effects.

[Brief description of the drawings]
FIG. 1 is a figure which shows the Example compound based on this invention.
FIG. FIG. 2 is a diagram showing Example compounds according to the present invention.
FIG. 3 is a figure which shows the Example compound based on this invention.
FIG. FIG. 4 is a view showing Example compounds according to the present invention.
FIG. FIG. 5 is a diagram showing Example compounds according to the present invention.
FIG. 6 is a figure which shows the Example compound based on this invention.
FIG. 7 is a figure which shows the Example compound based on this invention.
FIG. FIG. 8 is a diagram showing a sugar donor according to an example compound according to the present invention.
FIG. FIG. 9 is a diagram showing a sugar donor according to an example compound according to the present invention.

Claims (4)

With 21-position hydroxyl group of budesonide is modified with a sugar having a protecting group, said sugar is selected glucose, galactose, from the group consisting of mannose, rhamnose and fucose, the protecting group is toluoyl, furoyl group, Ba An anti-inflammatory agent comprising a budesonide derivative, which is selected from the group consisting of a reryl group, a tigloyl group and an isobutyryl group, as an active ingredient. The anti-inflammatory agent according to claim 1, which is an anti-inflammatory agent for topical application. The anti-inflammatory agent according to claim 2, which is a parenterally administered drug. The therapeutic agent for asthma administered by inhalation, the therapeutic agent for allergic rhinitis administered by nasal administration, the therapeutic agent for arthritis administered intraarticularly or by application, or the therapeutic agent for dermatitis by administration by application. 2. The anti-inflammatory agent according to 2.

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